Asthma and COPD

Question 1

What are the 2 phases of asthma and how does treatment vary for either?

Answer 1

1. Immediate-phase response: mostly bronchospasm to exposure of eliciting stimulus (early phase, so bronchodilators effective)
2. Late-phase response: several hours later due to inflammatory mediators and neuropeptide release from axon reflexes, results in bronchospasm/vasodilation/edema/muscous secretion (so need anti-inflammatory drug)

Question 2

What kinds of drugs might be asthma triggers?

Answer 2

Beta-blockers (cardioselective and non-selective)
Calcium antagonists
Dipyridamole
NSAID’s

Question 3

What are the differences when an asthma exacerbation is slower developing versus rapidly?

Answer 3

80-90% patients due to progressive inflammatory process = progression over hours or even weeks before functional deterioration (WBC in airways are eosinophils)

10% patients due to smooth muscle spasm = sudden onset less than 6 hours to hyperacute attack (WBC in airways are neutrophils)

Question 4

How is asthma diagnosed?

Answer 4

Need to exclude alternatives and patient needs to have episodic symptoms of airflow obstruction or BHR…that are reversible

Can use spirometry to demonstrate reversibility: FEV1 should increase at least 12% after using a short-acting inhaled beta2-agonist

Question 5

Physical exam may be normal in asthmatics, but what are some physical findings that would support asthma?

Answer 5

Wheezing sounds
Increased nasal secretion, mucosal swelling and nasal polyps
Hyperexpansion of thorax
Atopic dermatitis/eczema

Question 6

In general, what are the types of long-term control medications versus quick relief medications for asthma?

Answer 6

Long-term control: long-acting beta2 agonists (LABA), leukotriene modifiers, methylxantines, cromolyn, anti IgE, inhaled and systemic corticosteroids

Quick relief: short-acting beta2 agonists (SABA), anticholinergics, systemic corticosteroids

Question 7

What is the difference between an inhaler and a nebulizer?

Answer 7

Both are advantageous because drug goes directly to airways and can give high concentration locally (minimizing systemic effects)

Inhaler: is less efficient and requires technique, can use spacers to help make use easier (i.e. metered dose, breath activated, powder)

Nebulizer: converts solution into aerosol and can deliver higher doses to the lung, used in hospitals for status asthmaticus and severe asthma treatment
(not used as much because costly, inconvenient access and patient over-reliance)

Question 8

Inhaled Corticosteroids for asthmatics

Answer 8

Mechanism: decrease inflammatory response, edema and bronchial hyper-responsiveness (decrease mucus production, local prostaglandin and leukotriene production, upregulate adrenoceptor, long-term reduction of eosinophile and mast-cell infiltration)

Indication: best for LONG-TERM control for persistent asthma (reduces risk of death and exacerbations, but must be used REGULARLY to be effective)
*often combined with beta2-agonist or other agent

ADR: local risk of thrush and dysphonia (so rinse mouth), reflex cough and bronchospasm (due to increased tolerance… systemic effects are less severe than using systemic corticosteroids (i.e. HPA axis suppression, impaired growth in kids, dose-dependent dermal thinning)
-Reduce ADR by using spacer, rinse mouth, minimize dose, combine with LABA

*ICS contraindicated for growing kids
But low-medium doses have no adverse effects on bone mineral density, subcapsular cataracts, glaucoma, and HPA axis for kids… in adults there is dose-related risk of osteoporosis and ocular effects from high cumulative lifetime exposure

Question 9

Give examples of ICS meds for asthma

Answer 9

Fluticasone (Flovent)
Budesonide (Pulmicort)
Beclomethasone HFA (Ovar)
Flunisolide CFC (Aerobid)
Triamcinolone CFC (Azmacort)
Mometasone (Asmanex)
Ciclesonide HFA (Alvesco)

Question 10

Give examples of ICS and LABA combinations

Answer 10

Advair (Fluticasone/salmeterol)
Breo Ellipta (Fluticasone/vilanterol)
Symbicort (Budesonide/fomoterol)
Dulera (Mometasone/fomoterol)

Question 11

Give examples of LABAs used for asthma and ones for COPD

Answer 11

For asthma: Salmeterol, Formoterol, Arformoterol tartrate and Formoterol fumarate (both solutions for nebulizer)

For COPD: Indacaterol and Olodaterol (both of these can also be found in combo with anti-cholinergics)

Question 12

How should you NOT use long-acting beta2 agonists (LABAs)?

Answer 12

Do not substitute for anti-inflammatory therapy and is not for acute symptoms or exacerbations
Not for monotherapy but beneficial when added to ICS

i.e. Salmeterol and Formoterol mostly used as add-on therapy for asthmatics poorly controlled by medium-dose inhaled glucocorticosteroids

Question 13

What are the drug interaction concerns with LABA use?

Answer 13

Tolerance with chronic administration

Partial loss of protective effect against methacholine, histamine and exercise
Slight decrease to SABA response since LABA affects same receptor types (so may need to increase SABA by 1 puff)

BLACK BOX: LABA may increase chance of severe asthma episodes and death when episodes occur

Bronchodilator response NOT decreased

Also using CYP3A4 inhibitors can increase Salmeterol plasma levels

Heart problem concerns (prolonged QT, palpitations, tachycardia) so avoid Ketoconazole, Ritonavir, Atazanavir, Clarithromycin, Indinavir, Itraconazole, Nefazodone, Saquinavir, Telithromycin

Question 14

What are the NHLBI recommendations if asthma can not be controlled with ICS alone?

Answer 14

Increase ICS dose or can add a LABA to the ICS

Daily use of LABA limited: Salmeterol no more than 100mcg and Formoterol no more than 24mcg
LABA not to be used for acute symptoms, exacerbations or as monotherapy

Question 15

Give examples of Leukotriene receptor antagonists and generally what instances it is used for asthma

Answer 15

Montelukast (Singulair)
Zafirlukast (Accolate)
Zileuton (Zyflo)

Indication: Alternative treatment for mild persistent asthma in adjunct with ICS

Contraindication: pregnancy, beware in elderly, Zileuton for patients with active liver disease

ADR: HA, GI disturbances, liver toxicity for Zileuton and Zafirlukast, increased risk of respiratory infection for elderly for Zafirlukast and Montelukast

Question 16

How do Leukotriene Receptor Antagonists work?

Answer 16

Mechanism: competitive antagonist of leukotriene receptors D4 and E4 in bronchiolar muscle (results in bronchodilation)
*Zileuton doesn’t actually affect receptor, it inhibits 5-lipoxygenase which is necessary for leukotriene synthesis

Endogenous leukotrienes cause airway narrowing, which is sometimes seen with NSAIDs (i.e. NSAIDS free leukotrienes by inhibiting cycloxygenase and diverting arachidonic acid breakdown via lipoxygenase pathway)

Question 17

Which two Leukotrienes do you have to be concerned about certain drug interactions?

Answer 17

Zafirlukast and Zileuton

Zafirlukast: interacts with Warfarin and increases prothrombin time ~~35%; since food can reduce bioavailability should take 1 hour before or 2 hours after meals

Zileuton: doubles Theophylline concentration, doubles propranalol AUC (drug over time), increases prothrombin time with Warfarin

Question 18

Name two Methylxanthines

Answer 18

Theophylline

Aminophylline

Question 19

How do Methylxanthines work?

Answer 19

Indications: used as monotherapy and adjunctive therapy with ICS
Can be used on refractory patients
Can be taken orally, but also Aminophylline can be given as IV in severe asthma attacks

Mechanism: inhibits phosphodiesterase to increase cAMP levels, and increased cAMP relaxes smooth muscle = bronchodilation

Contraindications: children under 4, cardiac disease, HTN, hepatic impairment

ADRs: Generally worse with higher dosing starting with N/V, irritability, headache etc… then tachyarrhythmias, ventricaular arrhythmias and seizures
*Since minor effects don’t always occur before life-threatening ones (narrow window too), beware

Disease interactions: viral illness, CHF, cirrhosis, cigarette smoking etc.
Drug interactions: Cimetidine, Macrolides, Quinolones etc. also CYP1A2 and 3A4 substrates
*Because Methylxanthines have a narrow therapeutic window, have abundant interactions, and there are safer alternatives… so it is not used that often

Question 20

Mast Cell Stabilizers. Give 2 examples

Answer 20

i.e. Cromolyn sodium (Intal) and Nedocromil (Tilade)

Mechanism: stabilize mast cells to prevent release of inflammatory mediators

Indications: for patients under 20 with severe allergic disease and moderate asthma, or pregnancy since it is safe to use in pregnancy
(route is inhaled)
Safe…can be used as preventative before exercise or unavoidable allergen
*Not for acute asthma

ADR: cough, transient bronchospasm, throat irritation, bitter taste from Nedocromil

Question 21

What is Omalizumab (Xolair) reserved for in asthma patients?

Answer 21

Immunomodulator for persistent moderate-severe asthma in patients older than 12 who are not controlled with other therapies
Not 1st line and has a BLACK BOX: anaphylaxis risk after any dose

Mechanism: is a recombinant monoclonal antibody that binds to IgE on mast cells and basophils to limit release of allergy mediators

Question 22

When are systemic corticosteroids indicated for asthma patients?

Answer 22

For controlling chronic symptoms in people with SEVERE asthma or acute exacerbations
Meant to prevent progression of asthma exacerbation, prevent hospitalization or early relapse after emergency treatment

Mechanism: decrease inflammation by suppressing leukocyte migration and reversing the increased capillary permiability

Dosing: Use as low dose as possible and can use alternate day therapy to decrease toxicity, typically use only a short course depending on symptoms, need to taper off i.e. Prednisolone
Oral route preferred over IV unless it is an acute exacerbation
*If has received 3+ courses per year then need to RE-EVALULATE asthma plan

Question 23

What can be used for quick relief/acute asthma? Give specific examples

Answer 23

Use bronchodilators

Short-acting beta2-adrenoceptor agonist
i.e. Albuterol, Pirbuterol, Metaproterenol, Levalbuterol (R configuration racemic albuterol), Terbutaline

Question 24

How do beta2-adrenoceptor agonists work as bronchodilators?

Answer 24

Mechanism: there are beta2-adrenoceptors along airway smooth muscle that respond to epinephrine
Stimulation of these receptors leads to increased cAMP and smooth muscle relaxation = dilation

These are good since they are potent bronchodilators with little beta1 stimulating properties (fairly specific)

Beta2-adrenoceptor agonist may also slightly prevent mast cell activation

Question 25

What are the indications and ADR of using a beta2-adrenoceptor agonist?

Answer 25

Indications: for acute exacerbations to relieve bronchospasm, can also be used before exercise-induced bronchoconstriction
Can be used alone in mild asthma or in adjunct to corticosteroids (treats symptoms though and not underling disease/helping control symptoms)
*i.e. SABAs like albuterol are the only inhaled agents indicated for acute asthma attacks/rescue inhaler

ADR: fine tremor, tachycardia, hypokalemia at high dose, increased risk of exacerbation or decreased lung function (but not in prn use)

Question 26

How to determine if an asthma patient should get long-term control versus quick-relief?

Answer 26

Age and asthma severity determine whether the patient needs long-term control

EVERY patient should have quick-relief medication i.e. SABA prn for symptoms
*using SABA more than 2x a week for symptoms means control is inadequate and treatment needs to be increased

Question 27

What are the steps in the Stepwise Approach to initial management of asthma?
*this approach is useful for INITIAL management but not recommended for ongoing treatment decisions

Answer 27

Start: quick-relief short-acting bronchodilators as needed for symptoms

Step 1 Mild Intermittent: brief exacerbations = only need quick-relief, no daily meds

Step 2 Mild Persistent: exacerbations may affect activity and sleep = preferred treatment is low-dose ICS and beta2-agonist prn… alternative is cromolyn or nedocromil, leukotriene modifier or theophylline

Step 3 Moderate Persistent: daily symptoms with exacerbations that may affect activity/sleep and need daily use of SABA = preferred treatment is low-dose ICS and LABA with SABA prn… alternative treatment is medium-high dose ICS or low-dose ICS plus leukotriene modifier or theophylline

Step 4 Severe Persistent: continuous symptoms and limited physical activity = preferred treatment is medium-high dose ICS with LABA or if needed oral glucocorticosteroid

Question 28

What are the classifications of exacerbation severity for asthma?

Answer 28

Mild = dyspnea only with activity (PEF at least 70%)
Moderate = dyspnea interferes/limits activity (PEF 40-69%)
Severe = dyspnea at rest and interferes with talking (PEF less than 40%)
Subset of severe/Life-threatening = so much dyspnea can’t speak, sweating (PEF less than 25%)

Question 29

Based on asthma exacerbation severity classifications, what is the typical clinical course for each classification?

Answer 29

Mild = home management, use SABA (may use short course of oral corticosteroids)

Moderate = office or ED, SABA gives relief, and oral corticosteroids (symptoms last 1-2 days)

Severe = ED or hospitalization, partial relief from SABA so adjunct therapies are helpful, can use oral corticosteroids (symptoms last more than 3 days)

Life-threatening = ICU possibly, no/minimal SABA relief, adjunctive therapies helpful and use IV corticosteroids

Question 30

What is considered a good, incomplete and poor response to initial treatment of inhaled SABA for asthma exacerbation? What would the next steps be?

Answer 30

Good response: no wheezing/dyspnea with PEF greater than 80%
Call for follow-up and can continue SABA use or consider oral steroid burst

Incomplete response: persistent wheezing/dyspnea with PEF 50-79%, continue SABA and add oral steroid
Urgent same day follow-up

Poor response: marked wheezing/dyspnea with PEF less than 50%, immediate repeat of SABA with steroid burst
If severe distress then call doctor and go to ED (consider 911)

Question 31

What is the pathophysiology of COPD?

Answer 31

Usually from smoking or other damage from irritants

Destroyed sites recruit macrophages that release neutrophil chemotactic factors. Both macrophages and neutrophils release protease that breaks down c.t. and lung parenchyma = emphysema and mucus production.
Cytotoxic T cells also destroy alveolar wall by releasing prophyrins and TNF-alpha

Question 32

Why must you be cautious about giving O2 to a distressed COPD patient?

Answer 32

COPD patients chronically retain CO2 (obstructive lung disease impairs expiratory attempts)

Giving too much O2 will DEPRESS respiratory drive in these patients. Body is used to high CO2 and low O2, low O2 becomes the main drive for breathing (hypoxic drive)

Supplied oxygen increases alveolar oxygen tension and decreases breathing work needed to maintain arterial oxygen tension

Question 33

In general, what is typical COPD therapy and the principles behind it?

Answer 33

Foundation is with anticholinergic agents and beta2-agonists, a combination is better than either drug alone i.e. Albuterol AND Ipratropium

(antibiotics also used to reduce hospitalizations and for better resolution of symptoms in acute exacerbation of COPD)

*Adding a LABA (Salmeterol, Formoterol) helps lung function more compared to either beta2-agonist or steroid alone

Inhaled steroids only for moderate-severe restricted airflow if bronchodilator therapy has failed

Question 34

Give two examples of anticholinergics (antimuscarinics) that can be used for COPD.

Answer 34

Ipratropium and Tiotropium

Mechanism: parasympathetic vagal fibers cause bronchoconstriction with reflex stimulation of muscarinic receptors in airway walls, muscarinic antagonists block these receptors (especially M3) resulting in decreased bronchoconstrictor tone

Indications: relieve acute bronchospasm NOT for chronic therapy
Alternative for patients with beta2-agonist intolerance and treatment of choice for bronchospasm due to beta-blockers
*Ipratropium can provide additive effects to beta2-agonists in acute setting

Contraindications: glaucoma and pregnancy

Question 35

Name two combo COPD drugs (anticholinergic with LABA)

Answer 35

Indacaterol and Glycopyrronium (Ultibro Breezhaler)

Tiotropium and Olodaterol (Stiolto Respimat)

Question 36

What are the specific criteria for when to prescribe antibiotics to a COPD patient?

Answer 36

2/3 symptoms met: increased dyspnea, increased sputum volume, increased sputum purulence

Directed to most pathologies i.e. strep pneumoniae, haemophilus influenzae, moraxella catarrhalis

Question 37

What specific antibiotics are used for mild-moderate COPD exacerbations versus more severe COPD exacerbations?

Answer 37

Mild-moderate = doxycycline, sulfamethoxazole/trimethoprim, amoxicillin clavulanate, macrolides

Severe = antipseudomonal PCN, 3rd generation cephalosporins

Fluoroquinalones can be used for both mild-moderate and severe exacerbations